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An 89-year-old woman presented with a 6-year history of occasional episodes of impaired consciousness that were relieved by ingestion of a snack. Three months before presenting to our hospital, she had been hospitalized in a local hospital with subdural hematoma caused by a head contusion, where previously unrecognized hypoglycemia was discovered. Fasting plasma glucose concentration was 37 mg/dL, with a relatively high serum level of insulin (34.9 μU/mL). Computed tomography showed a 14 mm hyperenhancing tumor in the tail of the pancreas and she was referred to our hospital for further investigation. A prolonged fasting test revealed the plasma glucose concentration reduced to 43 mg/dL (2.4 mmol/L) at 8 h after the last meal. Serum insulin, proinsulin, and C-peptide concentrations were 21.1 μU/mL, 16.9 pmol/L, and 2.72 ng/mL, respectively. Subsequent intravenous administration of 1 mg of glucagon increased the plasma glucose concentration to 76 mg/dL (4.2 mmol/L). Moreover, the insulin-to-C-peptide molar ratio was 0.14. These data indicated the presence of insulinoma. Interestingly, serum anti-insulin antibodies were elevated (21.1 U/mL), although she had no history of taking exogenous insulin injection, alpha lipoic acid, or sulfhydryl group-containing agents. Human leukocyte antigen (HLA) typing revealed HLA-DRB1*0407 and HLA-DRB1*1405 alleles. Treatment with diazoxide prevented hypoglycemia, but was discontinued due to weight gain and leg edema. Elevated serum anti-insulin antibodies persisted almost 1 year after the diagnosis of insulinoma. We present a rare case of insulinoma concomitant with serum anti-insulin antibodies.

Abstract The effect of the menstrual cycle on fine motor skills is unclear. This study determined whether the menstrual cycle affected fine motor skills and related neural activities. Nineteen women with regular menstrual cycles were tested for fine motor skills using two types of tasks: grooved pegboard task (GPT), which evaluates motor control with high freedom of movements, and force modulation task (FMT), which evaluates more complex and fine motor control with low freedom of movements. We also assessed primary motor cortex intracortical circuits and sensorimotor integration using paired-pulse transcranial magnetic stimulation to reveal why the menstrual cycle affects fine motor skills. The present study indicated that fine motor skills assessed by FMT varied throughout the menstrual cycle while those measured by GPT did not. These results suggest that fine motor skills requiring more complex and fine control may be affected by the menstrual cycle. Additionally, changes in fine motor skills throughout the menstrual cycle may be associated with the severity of menstruation-related symptoms.

Abstract Monitoring and predicting fault slip behaviors in subduction zones is essential for understanding earthquake cycles and assessing future earthquake potential. We developed a data assimilation method for fault slip monitoring and the short-term prediction of slow slip events, and applied to the 2010 Bungo Channel slow slip event in southwest Japan. The observed geodetic data were quantitatively explained using a physics-based model with data assimilation. We investigated short-term predictability by assimilating observation data within limited periods. Without prior constraints on fault slip style, observations solely during slip acceleration predicted the occurrence of a fast slip; however, the inclusion of slip deceleration data successfully predicted a slow transient slip. With prior constraints to exclude unstable slip, the assimilation of data after slow slip event occurrence also predicted a slow transient slip. This study provides a tool using data assimilation for fault slip monitoring and prediction based on real observation data. Graphical Abstract

Electrocardiogram (ECG) is a powerful tool to detect cardiovascular diseases (CVDs) and health conditions. We proposed a new method for evaluating ECG for efficient medical diagnosis in daily life. By splitting the signal according to the cardiac activity cycle, the periodic split attractor reconstruction (PSAR) method is proposed with time embedding, including three types of splitting methods to show its chaotic domain characteristics. We merged the CVDs dataset and the obstructive sleep apnea syndrome (OSAS) first-lead ECG signal dataset to validate the performance of PSAR for diagnosis and health monitoring using PSAR density maps as SE-ResNet input features. PSAR under 3 split methods showed different sensitivities for different CVDs. While in OSAS monitoring, PSAR showed good ability to recognize sleep abnormalities.

Purpose: Hypofractionated radiation therapy (RT) was recommended for several cancer sites to reduce outpatient visits during the COVID-19 pandemic. This study aimed to identify the impact of the pandemic on hypofractionated RT for breast cancer in Japan. Methods and Materials: The monthly number of courses for hypofractionated and conventional RTs was counted using sample data sets from the National Database of Health Insurance Claims and Specific Health Checkups of Japan, a nationwide database accumulating insurance claims data comprehensively. Changes in the number of hypofractionated and conventional RTs were estimated using an interrupted time-series analysis. Results: The number of hypofractionated RT courses gradually increased before the pandemic in contrast to that of conventional RT courses, which gradually decreased. However, conventional RT remained outnumbered by hypofractionated RT throughout the observation period. After the outbreak of the pandemic, the use of hypofractionated RT significantly increased in April 2020 (1312 courses; 95% CI, 801-1823) but decreased in October 2020 (−601; 95% CI, −1111 to −92). Subgroup analysis by age and the number of beds in medical institutions revealed similar trends. Conclusions: Although conventional RT for breast cancer has been gradually replaced by hypofractionated RT, it remains predominant. The use of hypofractionated RT increased briefly early in the COVID-19 pandemic; however, this increase was not sustained, unlike in other countries. Considering the benefits of hypofractionated RT for breast cancer, its use should be encouraged in Japan.

Introduction: Endothelial cells have a crucial function in transporting and exchanging various nutrients. O-GlcNAcylation, mediated by O-GlcNAc transferase (OGT), involves the addition of N-acetylglucosamine to proteins and serves as an intracellular nutrient sensing mechanism. However, the role of O-GlcNAcylation in endothelial cells remains poorly understood. Objective: This study investigated the role of O-GlcNAcylation in endothelial cells. Methods: Endothelial-cell-specific Ogt -knockout mice (Ogt-ECKO) were generated by crossing Ogt-floxed mice (Ogt-flox) with VE-Cadherin Cre ERT2 mice. Ogt-ECKO mice and Ogt-flox control mice were subjected to a normal or high-fat diet, and their body weight, glucose metabolism, and lipid metabolism were examined. Results: Ogt-ECKO mice exhibited reduced body weight compared with Ogt-flox control mice under a high-fat diet. Lipid absorption was significantly impaired in Ogt-ECKO mice. Changes in the intercellular junctions of small intestinal lacteal endothelial cells from a button-like to a zipper-like configuration were observed. Furthermore, Ogt-ECKO mice showed decreased expression of VEGFR3. The administration of a nitric oxide donor restored lipid absorption and reversed the morphological alterations in Ogt-ECKO mice. Conclusions: These findings demonstrate the critical role of O-GlcNAcylation in endothelial cells in lipid absorption in the intestine through the modulation of lacteal junction morphology. These results provide novel insight into the metabolic regulatory mechanisms under physiological conditions and have implications for the development of new therapeutic strategies for obesity.

BackgroundBody temperature is the most-used noninvasive biomarker to determine menstrual cycle and ovulation. However, issues related to its low accuracy are still under discussion. ObjectiveThis study aimed to improve the accuracy of identifying the presence or absence of ovulation within a menstrual cycle. We investigated whether core body temperature (CBT) estimation can improve the accuracy of temperature biphasic shift discrimination in the menstrual cycle. The study consisted of 2 parts: experiment 1 assessed the validity of the CBT estimation method, while experiment 2 focused on the effectiveness of the method in discriminating biphasic temperature shifts. MethodsIn experiment 1, healthy women aged between 18 and 40 years had their true CBT measured using an ingestible thermometer and their CBT estimated from skin temperature and ambient temperature measured during sleep in both the follicular and luteal phases of their menstrual cycles. This study analyzed the differences between these 2 measurements, the variations in temperature between the 2 phases, and the repeated measures correlation between the true and estimated CBT. Experiment 2 followed a similar methodology, but focused on evaluating the diagnostic accuracy of these 2 temperature measurement approaches (estimated CBT and traditional oral basal body temperature [BBT]) for identifying ovulatory cycles. This was performed using urine luteinizing hormone (LH) as the reference standard. Menstrual cycles were categorized based on the results of the LH tests, and a temperature shift was identified using a specific criterion called the “three-over-six rule.” This rule and the nested design of the study facilitated the assessment of diagnostic measures, such as sensitivity and specificity. ResultsThe main findings showed that CBT estimated from skin temperature and ambient temperature during sleep was consistently lower than directly measured CBT in both the follicular and luteal phases of the menstrual cycle. Despite this, the pattern of temperature variation between these phases was comparable for both the estimated and true CBT measurements, suggesting that the estimated CBT accurately reflected the cyclical variations in the true CBT. Significantly, the CBT estimation method showed higher sensitivity and specificity for detecting the occurrence of ovulation than traditional oral BBT measurements, highlighting its potential as an effective tool for reproductive health monitoring. The current method for estimating the CBT provides a practical and noninvasive method for monitoring CBT, which is essential for identifying biphasic shifts in the BBT throughout the menstrual cycle. ConclusionsThis study demonstrated that the estimated CBT derived from skin temperature and ambient temperature during sleep accurately captures variations in true CBT and is more accurate in determining the presence or absence of ovulation than traditional oral BBT measurements. This method holds promise for improving reproductive health monitoring and understanding of menstrual cycle dynamics.

Introduction Insomnia is a common health problem and cognitive–behavioural therapy (CBT) is recommended as a treatment. As there is a critical shortage of CBT-trained therapists, we developed a digital CBT application (IIIP MED: Sleepy Med) as Software as a Medical Device for insomnia. This paper describes the study protocol for an exploratory randomised controlled trial (RCT) to evaluate effectiveness and safety of our developed digital CBT (dCBT) for 5 weeks compared with zolpidem tartrate for patients with insomnia disorder.Methods and analysis This proposed multicentre exploratory RCT will be conducted at the outpatient clinic of Chiba University Hospital, Akita University Hospital and Yoyogi Sleep Disorder Center, Japan. The study population comprises two parallel groups (dCBT and zolpidem) consisting of 15 participants each (n=30 in total) diagnosed with insomnia disorder who remain symptomatic at 4 weeks after sleep hygiene education. We will evaluate the effectiveness at baseline, week 5 (post-intervention) and week 10 (follow-up). The primary outcome will be the change of subjective sleep onset latency at week 5 from baseline. Secondary outcomes include sleep-related outcomes, such as objective sleep onset latency measured by mobile electroencephalography, functional improvement during the daytime and quality of life.Ethics and dissemination Ethics approval was granted by the Institutional Review Board of Chiba University Hospital (K2023001). All participants will be required to provide written informed consent. Results will be published in international journals.Trial registration number jRCT2032230353.

IntroductionRepetitive somatosensory stimulation (RSS) is a conventional approach to modulate the neural states of both the primary somatosensory cortex (S1) and the primary motor cortex (M1). However, the impact of RSS on skill acquisition and retention in sensorimotor adaptation remains debated. This study aimed to investigate whether whole-hand water flow (WF), a unique RSS-induced M1 disinhibition, influences sensorimotor adaptation by examining the hypothesis that whole-hand WF leads to M1 disinhibition; thereby, enhancing motor memory retention.MethodsSixty-eight young healthy participants were randomly allocated to three groups based on the preconditioning received before motor learning: control, whole-hand water immersion (WI), and whole-hand WF. The experimental protocol for all the participants spanned two consecutive days. On the initial day (day 1), baseline transcranial magnetic stimulation (TMS) assessments (T0) were executed before any preconditioning. Subsequently, each group underwent their respective 30 min preconditioning protocol. To ascertain the influence of each preconditioning on the excitability of the M1, subsequent TMS assessments were conducted (T1). Following this, all participants engaged in the motor learning (ML) of a visuomotor tracking task, wherein they were instructed to align a cursor with a target trajectory by modulating the pinch force. Upon completion of the ML session, final TMS assessments (T2) were conducted. All participants were required to perform the same motor learning 24 h later on day 2.ResultsThe results revealed that whole-hand WF did not significantly influence skill acquisition during sensorimotor adaptation, although it did reduce intracortical inhibition. This phenomenon is consistent with the idea that S1, rather than M1, is involved in skill acquisition during the early stages of sensorimotor adaptation. Moreover, memory retention 24 h after skill acquisition did not differ significantly across the three groups, challenging our initial hypothesis that whole-hand WF enhances memory retention throughout sensorimotor adaptation. This could be due to the inability of whole-hand WF to alter sensorimotor connectivity and integration, as well as the nature of the plastic response elicited by the preconditioning.DiscussionIn conclusion, these findings suggest that although whole-hand WF attenuates intracortical inhibition, it does not modulate skill acquisition or motor memory retention during sensorimotor adaptation.

Terahertz (THz) and sub-terahertz (sub-THz) waves are unexplored waves between the infrared and microwave ranges. This range features unique characteristics of both light resolution and electromagnetic wave transmission. Sub-THz waves are part of attractive new diagnostic methods for inner objects because they are safer than normal non-destructive inspection methods involving high energy, such as X-rays. In this study, a novel non-contact and non-destructive inspection method for reinforced concrete (RC) structures using sub-THz reflection imaging is proposed to inspect the deterioration of inaccessible damaged RC structures. The results of this study confirmed that the proposed sub-THz imaging method can detect cracks and voids in concrete, as well as in metals inside or behind the concrete, based on differences in reflectance. In addition, the camera-based measurement system makes real-time on-site field measurements possible.

Abstract Purpose Implant-supported immediately loaded fixed full-arch rehabilitation via All-on-four treatment yields good long-term results for both the maxilla and the mandible. However, the risk factors affecting long-term implant survival are unknown, and the long-term prognosis of All-on-four concept procedures in Japanese individuals has not been elucidated. We aimed to determine the cumulative implant survival rate after 3–17-year follow-up and identify the associated risk factors. Methods We analysed 561 cases (307 maxillae, 254 mandibles) with 2364 implants (1324 maxillae, 1040 mandibles) that received All-on-four treatment. We investigated the cumulative implant- and patient-level survival rates and various risk factors for implant failure. Statistical analysis was performed using the log-rank test for differences in Kaplan–Meier curves, univariate analysis using the Chi-square test, and multivariate analysis for risk factors affecting the survival rate. Results The cumulative survival rate was 94.4% by patient level and 97.4% by implant level for the maxilla, and 96.7% by patient level and 98.9% by implant for the mandible, with up to 17 years of follow-up. The maxillary survival rate at the implant level was significantly lower (p

Abstract In arterial myocytes, the canonical function of voltage-gated CaV1.2 and KV2.1 channels is to induce myocyte contraction and relaxation through their responses to membrane depolarization, respectively. Paradoxically, KV2.1 also plays a sex-specific role by promoting the clustering and activity of CaV1.2 channels. However, the impact of KV2.1 protein organization on CaV1.2 function remains poorly understood. We discovered that KV2.1 forms micro-clusters, which can transform into large macro-clusters when a critical clustering site (S590) in the channel is phosphorylated in arterial myocytes. Notably, female myocytes exhibit greater phosphorylation of S590, and macro-cluster formation compared to males. Contrary to current models, the activity of KV2.1 channels seems unrelated to density or macro-clustering in arterial myocytes. Disrupting the KV2.1 clustering site (KV2.1S590A) eliminated KV2.1 macro-clustering and sex-specific differences in CaV1.2 cluster size and activity. We propose that the degree of KV2.1 clustering tunes CaV1.2 channel function in a sex-specific manner in arterial myocytes.

Unawareness of postprandial hypoglycemia for 5 years was identified in a 66-year-old man at a local clinic. The patient was referred to our hospital because of this first awareness of hypoglycemia (i.e. lightheadedness and impaired consciousness) developing after lunch. In a 75 g oral glucose tolerance test, the plasma glucose concentration was decreased to 32 mg/dL (1.8 mmol/L) at 150 min with relatively high concentrations of insulin (8.1 μU/mL), proinsulin (70.3 pmol/L), and C-peptide (4.63 ng/mL). In a prolonged fasting test, the plasma glucose concentration was decreased to 43 mg/dL (2.4 mmol/L) at 66 h with an insulin concentration of 1.4 μU/mL and a C-peptide concentration of 0.49 ng/mL. Computed tomography showed an 18 mm hyperenhancing tumor in the uncinate process of the pancreas. A selective arterial calcium stimulation test showed an elevated serum insulin concentration in the superior mesenteric artery. The patient was then diagnosed with insulinoma and received pancreaticoduodenectomy. Continuous glucose monitoring (CGM) using the Dexcom G6 system showed unawareness of hypoglycemia mainly during the daytime before surgery. When the sensor glucose value was reduced to 55 mg/dL (3.1 mmol/L), the Dexcom G6 system emitted an urgent low glucose alarm to the patient four times for 10 days. Two months after surgery, an overall increase in daily blood glucose concentrations and resolution of hypoglycemia were shown by CGM. We report a case of insulinoma with unawareness of postprandial hypoglycemia in the patient. The Dexcom G6 system was helpful for assessing preoperative hypoglycemia and for evaluating outcomes of treatment by surgery.

Abstract Background Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described. Case presentation A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and “other iatrogenic immunodeficiency-associated lymphoproliferative disorder” (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD. Conclusions This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Abstract Angelman syndrome is a neurodevelopmental disorder caused by loss of function of the maternally expressed UBE3A gene. Treatments for the main manifestations, including cognitive dysfunction or epilepsy, are still under development. Recently, the Cl− importer Na+-K+-Cl− cotransporter 1 (NKCC1) and the Cl− exporter K+-Cl− cotransporter 2 (KCC2) have garnered attention as therapeutic targets for many neurological disorders. Dysregulation of neuronal intracellular Cl− concentration ([Cl−]i) is generally regarded as one of the mechanisms underlying neuronal dysfunction caused by imbalanced expression of these cation-chloride cotransporters (CCCs). Here, we analyzed the regulation of [Cl−]i and the effects of bumetanide, an NKCC1 inhibitor, in Angelman syndrome models (Ube3a m−/p+ mice). We observed increased NKCC1 expression and decreased KCC2 expression in the hippocampi of Ube3a m−/p+ mice. The average [Cl−]i of CA1 pyramidal neurons was not significantly different but demonstrated greater variance in Ube3a m−/p+ mice. Tonic GABAA receptor-mediated Cl− conductance was reduced, which may have contributed to maintaining the normal average [Cl−]i. Bumetanide administration restores cognitive dysfunction in Ube3a m−/p+ mice. Seizure susceptibility was also reduced regardless of the genotype. These results suggest that an imbalanced expression of CCCs is involved in the pathophysiological mechanism of Ube3a m−/p+ mice, although the average [Cl−]i is not altered. The blockage of NKCC1 may be a potential therapeutic strategy for patients with Angelman syndrome.

A 17-year-old boy was referred to our endocrinology clinic for a clinical investigation of hyperinsulinemia. An oral glucose tolerance test showed plasma glucose concentrations in the normal range. However, insulin concentrations were considerably elevated (0 min: 71 μU/mL; 60 min: 953 μU/mL), suggesting severe insulin resistance. An insulin tolerance test confirmed that he had insulin resistance. There was no apparent hormonal or metabolic cause, including obesity. The patient had no outward features of hyperinsulinemia, including acanthosis nigricans or hirsutism. However, his mother and grandfather also had hyperinsulinemia. Genetic testing showed that the patient (proband), his mother, and his grandfather had a novel p.Val1086del heterozygous mutation in exon 17 of the insulin receptor gene (INSR). Although all three family members have the same mutation, their clinical courses have been different. The onset of the mother’s diabetes was estimated at 50 years, whereas the grandfather developed diabetes at 77 years.

Abstract Various countries have reported a decrease in breast cancer surgeries during the coronavirus disease 2019 (COVID-19) pandemic; however, inconsistent results have been reported in Japan. This study revealed changes in the number of surgeries during the pandemic using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) from January 2015 to January 2021, where insurance claims data from Japan as a whole are comprehensively accumulated. The number of breast-conserving surgeries (BCS) without axillary lymph node dissection (ALND) significantly decreased in July (− 846; 95% confidence interval (CI) − 1190 to − 502) and October 2020 (− 540; 95% CI − 861 to − 218). No decrease was observed for other types of surgery, BCS with ALND, and mastectomy with or without ALND. In the age-specific subgroup analysis, significant and transient reduction in BCS without ALND was observed in all age groups (0–49, 50–69, and ≥ 70 years). The number of BCS without ALND significantly decreased for a relatively short period in the early pandemic stages, suggesting reduced surgery for patients with a relatively low stage of cancer. Some patients with breast cancer might have been left untreated during the pandemic, and an unfavorable prognosis would be a concern.

To investigate the effects of inert-gas addition on the dynamic behavior and propagation characteristics of spherically expanding hydrogen-air flames, the experiments of premixed combustion were performed in a closed chamber. The dynamic behavior of premixed flames was caught by high-speed Schlieren imaging, and the flame radius and propagation velocity were measured by analyzing the Schlieren photography. When the flame radius was sufficiently small, smooth flame surface was observed, where the flame stretch affected strongly the propagation velocity. From the correlation between the propagation velocity and flame stretch rate, we estimated the propagation velocity of unstretched flame and the Markstein length including thermal-expansion effects. When the flame radius was large, on the other hand, cellular surface induced by intrinsic instability was observed, and then the flame acceleration was confirmed. As the results, the critical flame radius corresponding to the occurrence of flame acceleration and the increment coefficient of propagation velocity were obtained. It was found that the increment coefficient became larger at low equivalence ratios, which was because the diffusive-thermal instability became stronger. Under the conditions of high concentration of inert gas, the increment coefficient of propagation velocity became smaller. This was because the burning velocity became lower by increasing the inert-gas concentration. Moreover, we obtained the increment coefficient normalized by the propagation velocity of unstretched flame. The normalized increment coefficient increased as the inert-gas concentration became higher, which indicated that the addition of inert gas promoted the instability of hydrogen flames. Based on the dynamic behavior and propagation characteristics of premixed flames, the parameters of flame acceleration model depending on the inert-gas concentration were obtained, and then the flame propagation velocity was predicted.

Abstract Transcranial random noise stimulation (tRNS) of the primary sensory or motor cortex can improve sensorimotor functions by enhancing circuit excitability and processing fidelity. However, tRNS is reported to have little effect on higher brain functions, such as response inhibition when applied to associated supramodal regions. These discrepancies suggest differential effects of tRNS on the excitability of the primary and supramodal cortex, although this has not been directly demonstrated. This study examined the effects of tRNS on supramodal brain regions on somatosensory and auditory Go/Nogo task performance, a measure of inhibitory executive function, while simultaneously recording event-related potentials (ERPs). Sixteen participants received sham or tRNS stimulation of the dorsolateral prefrontal cortex in a single-blind crossover design study. Neither sham nor tRNS altered somatosensory and auditory Nogo N2 amplitudes, Go/Nogo reaction times, or commission error rates. The results suggest that current tRNS protocols are less effective at modulating neural activity in higher-order cortical regions than in the primary sensory and motor cortex. Further studies are required to identify tRNS protocols that effectively modulate the supramodal cortex for cognitive enhancement.

Abstract A growing body of evidence suggests that excess stress could aggravate tumor progression. The paraventricular nucleus (PVN) of the hypothalamus plays an important role in the adaptation to stress because the hypothalamic–pituitary–adrenal (HPA) axis can be activated by inducing the release of corticotropin-releasing hormone (CRH) from the PVN. In this study, we used pharmacogenetic techniques to investigate whether concomitant activation of CRHPVN neurons could directly contribute to tumor progression. Tumor growth was significantly promoted by repeated activation of CRHPVN neurons, which was followed by an increase in the plasma levels of corticosterone. Consistent with these results, chronic administration of glucocorticoids induced tumor progression. Under the concomitant activation of CRHPVN neurons, the number of cytotoxic CD8+ T cells in the tumor microenvironment was dramatically decreased, and the mRNA expression levels of hypoxia inducible factor 1 subunit α (HIF1α), glucocorticoid receptor (GR) and Tsc22d3 were upregulated in inhibitory lymphocytes, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). Furthermore, the mRNA levels of various kinds of driver molecules related to tumor progression and tumor metastasis were prominently elevated in cancer cells by concomitant activation of CRHPVN neurons. These findings suggest that repeated activation of the PVN-CRHergic system may aggravate tumor growth through a central–peripheral-associated tumor immune system.

Abstract A growing body of evidence suggests that intractable pain reduces both the quality of life and survival in cancer patients. In the present study, we evaluated whether chronic pain stimuli could directly affect cancer pathology using tumor-bearing mice. For this purpose, we used two different models of chronic pain in mice, neuropathic pain and persistent postsurgical pain, with Lewis lung carcinoma (LLC) as tumor cells. We found that tumor growth was dramatically promoted in these pain models. As well as these pain models, tumor growth of LLC, severe osteosarcoma (AXT) and B16 melanoma cells was significantly promoted by concomitant activation of sensory neurons in AAV6-hM3Dq-injected mice treated with the designer drug clozapine-N-oxide (CNO). Significant increases in mRNA levels of vascular endothelial growth factor-A (Vegfa), tachykinin precursor 1 (Tac1) and calcitonin-related polypeptide alpha (Calca) in the ipsilateral side of dorsal root ganglion of AAV6-hM3Dq-injected mice were observed by concomitant activation of sensory neurons due to CNO administration. Moreover, in a model of bone cancer pain in which mice were implanted with AXT cells into the right femoral bone marrow cavity, the survival period was significantly prolonged by repeated inhibition of sensory neurons of AAV6-hM4Di-injected mice by CNO administration. These findings suggest that persistent pain signals may promote tumor growth by the increased expression of sensory-located peptides and growth factors, and controlling cancer pain may prolong cancer survival.

Middle meningeal artery embolization (MMAE) for chronic subdural hematoma (CSDH) is a novel, minimally invasive treatment. The indications and treatment practices for MMAE are variable and remain controversial. This study aimed to evaluate a strategy involving sequential MMAE after burr hole surgery for treating recurrent CSDH. We performed a retrospective analysis of data from consecutive patients who had undergone MMAE using liquid embolic agents within approximately 2 weeks after burr hole surgery for recurrent CSDH from September 2020 to March 2022. We analyzed patient characteristics, procedural details, CSDH recurrence after MMAE, surgical rescue, and complications. Six of the nine patients who underwent MMAE for CSDH recurrence were male, and the median age was 85 (range, 70-94) years. Five of the nine patients were being administered antithrombotic agents. The median duration between the burr hole surgery and MMAE procedure was 10 (range, 3-25) days. Anterior and posterior convexity branches were targeted for embolization using low-concentration N-butyl cyanoacrylate (NBCA), and the abnormal vascular networks with a cotton wool appearance disappeared after embolization in all cases. The NBCA distribution was observed by high-resolution computed tomography during the procedure; in three of nine cases, the NBCA penetrated not only the MMA but also the inner membrane. No recurrence, surgical rescue, or complications were observed in any patient during the median follow-up period of 3 months. As a minimally invasive treatment for recurrent CSDH, sequential MMAE after burr hole surgery may be a safe and effective option for preventing recurrence.

Abstract Background Mature teratomas are benign germ cell tumors. On rare occasions, they have been associated with somatic malignancies and are termed rare germ cell tumors with a somatic-type malignancy (GCTSM). Mature teratomas commonly comprise adenocarcinomas; only seven previous cases of mature teratomas with neuroendocrine tumors have been reported to date. Here, we report a patient with a neuroendocrine tumor whithin a mature teratoma. Case presentation A 26-year-old man visited our department complaining of chest tightness. Contrast-enhanced computed tomography (CT) scans showed a strongly enhanced lesion within a 10-cm encapsulated cystic lesion in the anterior mediastinum. Positron emission tomography (PET) scans showed no areas of significant 18F-fluorodeoxyglucose (18F-FDG) accumulation. He underwent complete tumor resection via the transsternal approach. Histopathological examination of the specimen indicated a neuroendocrine tumor contained within a mature teratoma. Conclusions In this case, a neuroendocrine tumor was contained within a mature teratoma. Our patient had no specific symptoms and his serum markers were within the normal range. Although PET is beneficial for diagnosing other GCTSM, it is not useful in detecting a neuroendocrine tumor. Therefore, the preoperative diagnosis of neuroendocrine tumors contained within mature teratomas remains challenging. However, GCTSM should be suspected in patients exhibiting CT findings of a mediastinal tumor, measuring ≥ 6 cm, in addition to characteristic GCTSM findings. Moreover, surgery should be performed carefully in such cases.

Abstract Background Many non–small cell lung cancer (NSCLC) tumors present complex histology with various components. The effects of the lepidic growth component (LGC) on the prognosis of NSCLC have not been investigated. Here, we investigated whether an LGC is a relevant prognostic factor for NSCLC. Methods This study retrospectively investigated the clinicopathologic characteristics of 379 patients with NSCLC ≤3 cm who underwent complete surgical resection between 2004 and 2016 at the University of Yamanashi Hospital. The histologic subtypes were classified into NSCLC with or without an LGC. We evaluated the effect of an LGC on the clinicopathologic features and 5‐year overall survival of patients with NSCLC. Results On final pathology, 214 (56%) of 379 patients had an LGC, and 165 (44%) did not. Sex, smoking history, ground‐glass opacity component, pathologic invasive size, lymph node metastasis, pleural invasion, vessel invasion, pathologic stage, and histologic type were significantly different between the groups. Multivariate analysis of 5‐year overall survival, identified age (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.035–1.105; p

Collagen is a vital component of the extracellular matrix in animals. Collagen forms a characteristic triple helical structure and plays a key role in supporting connective tissues and cell adhesion. The ability to control the collagen triple helix structure is useful for medical and conformational studies because the physicochemical properties of the collagen rely on its conformation. Although some photo-controllable collagen model peptides (CMPs) have been reported, satisfactory photo-control has not yet been achieved. To achieve this objective, detailed investigation of the isomerization behavior of the azobenzene moiety in CMPs is required. Herein, two CMPs were attached via an azobenzene linker to control collagen triple helix formation by light irradiation. Azo-(PPG)10 with two (Pro-Pro-Gly)10 CMPs linked via a photo-responsive azobenzene moiety was designed and synthesized. Conformational changes were evaluated by circular dichroism and the cis-to-trans isomerization rate calculated from the absorption of the azobenzene moiety indicated that the collagen triple helix structure was partially disrupted by isomerization of the internal azobenzene.

This study focused on the biogas-air premixed flames formed on a flat burner under the conditions of oxygen enrichment and hydrogen addition to improve the combustion characteristics of biogas-air premixtures. The objectives of this study were to study the effects of oxygen concentration in the oxidizer and hydrogen concentration in the fuel on the intrinsic instability of premixed flames, and to study the effects of flame instability on the flame shape and behavior. Photographs of flames were taken by a digital single-lens reflex camera, and the emission of light from flames was acquired by a photodiode. Cellular structures of flame fronts were identified by photographs taken. The light emission was analyzed to clarify the fluctuating characteristics by time series analysis. Cellular flames were observed at equivalent ratios near the lower flammable limit under the conditions of oxygen enrichment and hydrogen addition. The cellular-flame range decreased with increasing oxygen concentration in the oxidizer and increased with increasing hydrogen concentration in the fuel. Chaotic time series analysis was performed on the light emission to reconstruct the attractor. As a result, regardless of the oxygen concentration, the attractor at the lower flammable limit exhibited quasi-periodic behavior slightly. On the other hand, the attractor near the lower flammable limit became more complex with increasing hydrogen concentration in the fuel. These results indicated that the oxygen enrichment and hydrogen addition affected the intrinsic instability and flame shape and behavior.

BackgroundIntroducing telemedicine in outpatient treatment may improve patient satisfaction and convenience. However, the optimal in-person visit interval for video-based telemedicine among patients with hypertension remains unreported in Japan. ObjectiveWe determined the optimal in-person visit interval for video-based telemedicine among patients with hypertension. MethodsThis was a cluster randomized controlled noninferiority trial. The target sites were 8 clinics in Japan that had a telemedicine system, and the target patients were individuals with essential hypertension. Among patients receiving video-based telemedicine, those who underwent in-person visits at 6-month intervals were included in the intervention group, and those who underwent in-person visits at 3-month intervals were included in the control group. The follow-up period of the participants was 6 months. The primary end point of the study was the change in systolic blood pressure, and the secondary end points were the rate of treatment continuation after 6 months, patient satisfaction, health economic evaluation, and safety evaluation. ResultsOverall, 64 patients were enrolled. Their mean age was 54.5 (SD 10.3) years, and 60.9% (39/64) of patients were male. For the primary end point, the odds ratio for the estimated difference in the change in systolic blood pressure between the 2 groups was 1.18 (90% CI –3.68 to 6.04). Notably, the criteria for noninferiority were met. Patient satisfaction was higher in the intervention group than in the control group. Furthermore, the indirect costs indicated that lost productivity was significantly lesser in the intervention group than in the control group. Moreover, the treatment continuation rate did not differ between the intervention and control groups, and there were no adverse events in either group. ConclusionsBlood pressure control status and safety did not differ between the intervention and control groups. In-person visits at 6-month intervals may cause a societal cost reduction and improve patient satisfaction during video-based telemedicine. Trial RegistrationUMIN Clinical Trials Registry (UMIN-CTR) UMIN000040953; https://tinyurl.com/2p8devm9

Early implant failure occurring within 1 year after implantation has been attributed to various factors. Particularly, early failure can lead to challenges in maintaining a full-arch prosthetic device, necessitating prompt intervention, including reoperation. This study aimed to retrospectively examine implant- and patient-related factors and the effects of photofunctionalisation associated with early failure in patients who underwent treatment using the all-on-four concept in both the maxilla and mandible. We conducted this retrospective study comprising 561 patients with 2364 implants who underwent implant-supported immediate loading with fixed full-arch rehabilitation using the all-on-four concept. We aimed to assess the survival rate within 1 year after implantation and determine the risk factors influencing early failure. The 1-year survival rates after implantation were 97.1% (patient level) and 98.9% (implant level) for the maxilla and 98.5% (patient level) and 99.6% (implant level) for the mandible. There was a significant difference in the implant-level survival rates between the maxilla and mandible, with a lower rate in the maxilla (p = 0.043). The risk factors associated with early implant failure according to the all-on-four concept included the maxilla (implant level) and smoking (patient level). We could not find a significant effect of photofunctionalisation on early failure (p = 0.25) following this treatment protocol.

Comprehensive, long-term studies on patient-reported outcomes for two-implant overdentures with magnetic attachments using immediate or conventional loading methods are lacking. This study aimed to provide 5-year follow-up data comparing patient-reported outcomes for mandibular overdentures supported by two implants with magnetic attachments under immediate or conventional loading. Nineteen edentulous mandible patients were randomly assigned to immediate (IG) or conventional loading groups (CG). Two implants were placed with prostheses, loaded on the same day (immediate) or three months later (conventional). Participants completed questionnaires (oral health-related quality of life (OHRQoL), patient general satisfaction, and patient’s denture assessment (PDA)) at baseline and yearly intervals for 5 years. Results showed no significant differences between IG and CG throughout the study. However, the within-group analysis revealed significant improvements in OHRQoL, patient satisfaction, and all PDA domains from the baseline to years 1–5. Regarding patient satisfaction, significant differences were observed between T1, T2, and T3 when compared with T0 of IG and T1-T0 of CG. Regarding PDA results of T4-T5, IG exhibited several significant differences compared to CG. In conclusion, this study suggests that two-implant overdentures with magnetic attachments, whether immediately or conventionally loaded, improve patient-reported outcomes. Immediate loading may have prolonged effects on the improvement of patient-reported outcomes.

Maxillary sinus augmentation with a lateral approach (MSA) is a well-established treatment. In this prospective study, we evaluated risk factors for postoperative bone graft displacement and reported the clinical application of long-term resorbable L-lactic acid/-caprolactone (PLA/PCL) as a barrier membrane to cover the open window in the lateral wall in MSA. Twenty-four patients underwent MSA according to the relevant criteria; CT data obtained before and 1 week (1 w) and 5–6 months (5 m) post-MSA, bone height changes, bone height reduction rates at 1 w and 5 m post-MSA, bone graft displacement measurements, and risk factors were examined. All patients showed bone height increments (p < 0.005). However, no difference was observed between 1 w and 5 m post-MSA. Bone graft displacement was observed in eight patients; the reduction rate from 1 w to 5 m post-MSA was 8.38% ± 4.88%. Sex, septa, maxillary sinus floor–palatal bone distance, and maxillary sinus floor–maxillary ostium distance were associated with bone graft displacement (p < 0.05). The height from the maxillary sinus floor to the palatal bone and the sinus angle influenced the augmentation degree (p < 0.05). The PLA/PCL membrane is compared favorably with other membranes and may be useful as a barrier membrane for the MSA open window.

Abstract Recent research has suggested that the mesolimbic dopamine network that mainly terminates in the nucleus accumbens may positively control the peripheral immune system. The activation of dopamine receptors in neurons in the nucleus accumbens by the release of endogenous dopamine is thus expected to contribute to efferent immune regulation. As in the stimulation of Gs-coupled dopamine D1-receptors or Gi-coupled D2-receptors by endogenous dopamine, we investigated whether specific stimulation of dopamine D1-receptor-expressing neurons or inhibition of dopamine D2-receptor-expressing neurons in the nucleus accumbens could produce anti-tumor effects and improve the immune system in transgenic mice using pharmacogenetic techniques. Repeated stimulation of D1-receptor-expressing neurons in either the medial shell, lateral shell or core regions of the nucleus accumbens significantly decreased tumor volume under a state of tumor transplantation, whereas repeated suppression of D2-receptor-expressing neurons in these areas had no effect on this event. The number of splenic CD8+ T cells was significantly increased following repeated stimulation of D1-receptor-expressing neurons in the nucleus accumbens of mice with tumor transplantation. Furthermore, this stimulation produced a significant reduction in the population of splenic CD8+ T cells that expressed immune checkpoint-related inhibitory receptors, PD-1, TIM-3 and LAG-3. These findings suggest that repeated stimulation of D1-receptor-expressing neurons (probably D1-receptor-expressing medium spiny neurons) in the nucleus accumbens suppressed tumor progression and improved the immune system by suppressing the exhaustion of splenic CD8+ T cells.

When storing images and videos on a limited storage device or transmitting them over a narrow-band network, an effective approach is to detect the necessary parts and process them preferentially. Visual saliency has often been used for this purpose, and many methods have been proposed to detect salient objects. However, a salient object is not necessarily the primary subject in an image. Determining the important regions in an image is not clear or easy to achieve because it generally depends on the context of the image. In this study, we propose a novel framework for detecting important image regions. We leverage an image-captioning technique because it interprets the context of an image when generating sentences. The proposed method determines those important regions that are closer to the level of human sensitivity by exploiting semantic information from the image captioning. To evaluate the effectiveness of the proposed method, we created a dataset that defines important regions within images based on experiments using subjective evaluation. Applying this dataset, we confirmed that the accuracy of the proposed approach was higher than that of conventional saliency-based object detection methods.

To clarify the effects of long-term administration of SGLT2 inhibitor, a hypoglycemic agent, on basal sympathetic nerve activity (SNA) and on SNA under development of insulin resistance, we measured peripheral SNA in response to a glucose load in standard chow- (SCF) and high-fat-fed (HFF) rats treated with or without dapagliflozin for 7 weeks. We conducted an intravenous glucose administration (IVGA), and evaluated SNA microneurographically recorded in the unilateral sciatic nerve. Dapagliflozin did not affect the steady state action potential (AP) rate just before the IVGA (baseline) in both the SCF and HFF rats. After the IVGA, in the SCF rats, the AP rate in dapagliflozin-treated group transiently decreased within 20 min after the IVGA, and was significantly lower (P

Background/purpose: Few studies have comprehensively assessed long-term patient-reported outcomes for overdentures supported by two immediate implants. The purpose of the study was to evaluate patient-reported outcomes of immediately loaded two-implant-supported overdentures retained by ball attachments over a 5-year evaluation period. Material and methods: Nineteen participants with edentulous mandibles were provided with immediately loaded two-unsplinted-implant-supported overdentures retained by ball attachments. The participants completed the Japanese version of the Oral Health Impact Profile (OHIP)-EDENT-19 and the Patient's Denture Assessment (PDA). Additionally, patient satisfaction was measured by a 100-mm visual analog scale (VAS). Measurements were performed at baseline, and at 1 and 5 years following implant surgery. Results: Seventeen participants and 14 participants were evaluated at the 1-year and 5-year assessment, respectively. Considering the OHIP-EDENT-19, there was a significant decrease in the total (p = 0.046), “functional limitation” (p = 0.021), and “physical disability” (p = 0.034) scores at 1 year and the total (p = 0.045) and “physical disability” (p = 0.024) scores at 5 years following surgery, compared to the baseline scores. Considering the PDA, there was a significant increase in the “function” (p = 0.038) and “lower denture” (p = 0.003) scores at 1 year and the “function” (p = 0.032), “lower denture” (p = 0.008), and “esthetic and speech” (p = 0.043) scores at 5 years following surgery, compared to the baseline scores. Patient satisfaction at 1 year following surgery was significantly greater than that at baseline (p = 0.005). Conclusion: Immediately loaded two-unsplinted-implant-supported overdentures retained by ball attachments improved the oral health-related quality of life and self-assessment of dentures by the patients up to 5 years following implant surgery.

Background/purpose: No studies have comprehensively assessed short-term patient-reported outcomes after the provision of overdentures supported by two immediate implants. The purpose of this study was to evaluate short-term patient-reported outcomes for mandibular overdentures retained by ball attachments on two immediately loaded implants. Materials and methods: Nineteen participants with mandibular edentulism were provided with overdentures retained by ball attachments on two immediately loaded, unsplinted implants. The participants' self-assessment of their dentures and oral health-related quality of life were evaluated with the 22-item Patient's Denture Assessment (PDA), and the 19-item Japanese version of the Oral Health Impact Profile (OHIP-EDENT), respectively. Patient satisfaction was measured on a 100 mm visual analogue scale. Assessments were conducted at baseline, and at 1 and 6 months after implant surgery. Results: There were significant increases in the PDA “Lower denture” (P = 0.009) at 1 month, as well as “Function” (P = 0.002) and “Lower denture” (P = 0.009) scores at 6 months. Patient satisfaction was also significantly increased at 1 month (P = 0.007) and 6 months (P ≤ 0.000). Significant decreases were observed in the OHIP-EDENT “Physical pain” (P = 0.046) score at 1 month, as well as the summary score (P = 0.033), “Functional limitation” (P = 0.020) and “Psychological discomfort” (P = 0.019) scores at 6 months. Conclusion: The use of two immediately loaded implants for lower mandibular complete overdentures is associated with improvements in patient's self-assessment of dentures, satisfaction, and oral health-related quality of life, up to 6 months after implant surgery.

Abstract Emerging evidence suggests that the mesolimbic dopaminergic network plays a role in the modulation of pain. As chronic pain conditions are associated with hypodopaminergic tone in the nucleus accumbens (NAc), we evaluated the effects of increasing signaling at dopamine D1/D2-expressing neurons in the NAc neurons in a model of neuropathic pain induced by partial ligation of sciatic nerve. Bilateral microinjection of either the selective D1-receptor (Gs-coupled) agonist Chloro-APB or the selective D2-receptor (Gi-coupled) agonist quinpirole into the NAc partially reversed nerve injury-induced thermal allodynia. Either optical stimulation of D1-receptor-expressing neurons or optical suppression of D2-receptor-expressing neurons in both the inner and outer substructures of the NAc also transiently, but significantly, restored nerve injury-induced allodynia. Under neuropathic pain-like condition, specific facilitation of terminals of D1-receptor-expressing NAc neurons projecting to the VTA revealed a feedforward-like antinociceptive circuit. Additionally, functional suppression of cholinergic interneurons that negatively and positively control the activity of D1- and D2-receptor-expressing neurons, respectively, also transiently elicited anti-allodynic effects in nerve injured animals. These findings suggest that comprehensive activation of D1-receptor-expressing neurons and integrated suppression of D2-receptor-expressing neurons in the NAc may lead to a significant relief of neuropathic pain.

To investigate the dynamic behavior and flame acceleration of spherically expanding hydrogen flames under the low-pressure conditions, the deflagration experiments were conducted in a closed combustion chamber. The dynamic behavior of hydrogen flames was observed by high-speed Schlieren imaging, and the flame radius and propagation velocity were measured by analyzing the Schlieren photography. When the flame radius was sufficiently small, smooth flame surface was observed, where flame stretching affected strongly the propagation velocity. From the correlation between the flame stretch rate and the propagation velocity, we estimated the Markstein length and Markstein number. When the flame radius was large, on the other hand, cellular surface was observed and the flame acceleration was confirmed. As a result, the critical flame radius corresponding to the occurrence of flame acceleration and the increment coefficient of propagation velocity were obtained. Under the low-pressure conditions, the dynamic behavior of hydrogen flames became weaker and the increment coefficient of propagation velocity became smaller. This was because the intrinsic instability was weakened by increasing the preheat zone thickness. It was also found that the increment coefficient became larger at lower equivalence ratios, which was because the diffusive-thermal instability became stronger. Moreover, the effects of preheat zone thickness on the flame acceleration was elucidated. We obtained the correlation between the normalized increment coefficient of propagation velocity and the preheat zone thickness. Based on the characteristics of dynamic behavior of hydrogen flames, the parameters of flame acceleration model depending on the initial pressure was obtained, and then the flame propagation velocity under the low-pressure conditions were predicted.

Abstract Background The role of various serum tumor markers (TMs) has been reported in non‐small cell lung cancer (NSCLC). However, the prognosis of patients with multiple TM‐negative NSCLC remain unclear. Aims This study aimed to describe the characteristics and outcomes of patients with NSCLC undergoing surgery and to investigate their prognostic association with preoperative serum TM‐negative cases. Methods and results We retrospectively evaluated 442 patients who underwent complete resection of stage I NSCLC between January 2004 and December 2019. These 442 patients were classified into a group whose preoperative serum levels of carcinoembryonic antigen (CEA), cytokeratin‐19 fragment (CYFRA21‐1), carbohydrate antigen 19‐9 (CA19‐9), and squamous cell carcinoma antigen (SCC Ag) were all negative (TM‐negative group; n = 249, 56%) and a group with at least one positive marker (TM‐positive group; n = 193, 44%). Among all patients, the TM‐negative group showed higher 5‐year recurrence‐free survival (RFS) (92.6% vs. 79.1%; p

Abstract Chronic postsurgical pain (CPSP) is a serious problem. We developed a mouse model of CPSP induced by electrocautery and examined the mechanism of CPSP. In this mouse model, while both incision and electrocautery each produced acute allodynia, persistent allodynia was only observed after electrocautery. Under these conditions, we found that the mRNA levels of Small proline rich protein 1A (Sprr1a) and Annexin A10 (Anxa10), which are the key modulators of neuropathic pain, in the spinal cord were more potently and persistently increased by electrocautery than by incision. Furthermore, these genes were overexpressed almost exclusively in chronic postsurgical pain-activated neurons. This event was associated with decreased levels of tri-methylated histone H3 at Lys27 and increased levels of acetylated histone H3 at Lys27 at their promoter regions. On the other hand, persistent allodynia and overexpression of Sprr1a and Anxa10 after electrocautery were dramatically suppressed by systemic administration of GSK-J4, which is a selective H3K27 demethylase inhibitor. These results suggest that the effects of electrocautery contribute to CPSP along with synaptic plasticity and epigenetic modification.

Background: The coronavirus disease-2019 (COVID-19) pandemic significantly affected management of cardiovascular disease around the world. The effect of the pandemic on volume of cardiovascular diagnostic procedures is not known. Objectives: This study sought to evaluate the effects of the early phase of the COVID-19 pandemic on cardiovascular diagnostic procedures and safety practices in Asia. Methods: The International Atomic Energy Agency conducted a worldwide survey to assess changes in cardiovascular procedure volume and safety practices caused by COVID-19. Testing volumes were reported for March 2020 and April 2020 and were compared to those from March 2019. Data from 180 centers across 33 Asian countries were grouped into 4 subregions for comparison. Results: Procedure volumes decreased by 47% from March 2019 to March 2020, showing recovery from March 2020 to April 2020 in Eastern Asia, particularly in China. The majority of centers cancelled outpatient activities and increased time per study. Practice changes included implementing physical distancing and restricting visitors. Although COVID testing was not commonly performed, it was conducted in one-third of facilities in Eastern Asia. The most severe reductions in procedure volumes were observed in lower-income countries, where volumes decreased 81% from March 2019 to April 2020. Conclusions: The COVID-19 pandemic in Asia caused significant reductions in cardiovascular diagnostic procedures, particularly in low-income countries. Further studies on effects of COVID-19 on cardiovascular outcomes and changes in care delivery are warranted.

Sustained peripheral somatosensory stimulations, such as high-frequency repetitive somatosensory stimulation (HF-RSS) and vibrated stimulation, are effective in altering the balance between excitation and inhibition in the somatosensory cortex (S1) and motor cortex (M1). A recent study reported that whole-hand water flow (WF) stimulation induced neural disinhibition in the M1. Based on previous results, we hypothesized that whole-hand WF stimulation would lead to neural disinhibition in the S1 because there is a strong neural connection between M1 and S1 and aimed to examine whether whole-hand WF stimulation would change the neural balance between excitation and inhibition in the S1. Nineteen healthy volunteers were studied by measuring excitation and inhibition in the S1 before and after each of the four 15-min interventions. The excitation and inhibition in the S1 were assessed using somatosensory evoked potentials (SEPs) and paired-pulse inhibition (PPI) induced by single- and paired-pulse stimulations, respectively. The four interventions were as follows: control, whole-hand water immersion, whole-hand WF, and HF-RSS. The results showed no significant changes in SEPs and PPI following any intervention. However, changes in PPI with an interstimulus interval (ISI) of 30 ms were significantly correlated with the baseline value before whole-hand WF. Thus, the present findings indicated that the whole-hand WF stimulation had a greater decreased neural inhibition in participants with higher neural inhibition in the S1 at baseline. Considering previous results on M1, the present results possibly show that S1 has lower plasticity than M1 and that the duration (15 min) of each intervention may not have been enough to alter the balance of excitation and inhibition in the S1.

BackgroundVirtual reality (VR) exergaming is a new intervention strategy to help humans engage in physical activity to enhance mood. VR exergaming may improve both mood and executive function by acting on the prefrontal cortex, expanding the potential benefits. However, the impact of VR exergaming on executive function has not been fully investigated, and associated intervention strategies have not yet been established. ObjectiveThis study aims to investigate the effects of 10 minutes of VR exergaming on mood and executive function. MethodsA total of 12 participants played the exergame “FitXR” under 3 conditions: (1) a VR exergame condition (ie, exercise with a head-mounted display condition [VR-EX]) in which they played using a head-mounted display, (2) playing the exergame in front of a flat display (2D-EX), and (3) a resting condition in which they sat in a chair. The color-word Stroop task (CWST), which assesses executive function; the short form of the Profile of Mood States second edition (POMS2); and the short form of the Two-Dimensional Mood Scale (TDMS), which assess mood, were administered before and after the exercise or rest conditions. ResultsThe VR-EX condition increased the POMS2 vigor activity score (rest and VR-EX: t11=3.69, P=.003) as well as the TDMS arousal (rest vs 2D-EX: t11=5.34, P

L-menthol is known to activate transient receptor potential melastatin 8 (TRPM8) and induce analgesia to thermal stimuli. However, since thermal stimulation leads to the interaction among the other TRP channels, it was unclear whether L-menthol causes analgesia to stimuli other than thermal stimuli. Therefore, we aimed to investigate whether activating TRPM8 via topical application of 10% menthol solution attenuates pain-related somatosensory-evoked potentials (pSEPs) and affects numerical rating scale (NRS) score using intra-epidermal electrical stimulation (IES). We applied 10% L-menthol or control solution on the dorsum of the right hand of 25 healthy participants. The pSEP and NRS, elicited by IES, and sensory threshold were measured before and after each solution was applied. The results showed that the topical application of 10% L-menthol solution significantly reduced N2–P2 amplitude in pSEPs compared with the control solution. Moreover, the N2 latency was significantly prolonged upon the topical application of L-menthol solution. NRS scores were similar under both conditions. These results suggest that topical application of L-menthol does not alter subjective sensation induced using IES, although it may attenuate afferent signals at free nerve endings even with stimuli that do not directly activate TRP channels.

A growing theme in chemistry is the joining of multiple organic molecular building blocks to create functional molecules. Diverse derivatizable structures—here termed “scaffolds” comprised of “hubs”—provide the foundation for systematic covalent organization of a rich variety of building blocks. This review encompasses 30 tri- or tetra-armed molecular hubs (e.g., triazine, lysine, arenes, dyes) that are used directly or in combination to give linear, cyclic, or branched scaffolds. Each scaffold is categorized by graph theory into one of 31 trees to express the molecular connectivity and overall architecture. Rational chemistry with exacting numbers of derivatizable sites is emphasized. The incorporation of water-solubilization motifs, robust or self-immolative linkers, enzymatically cleavable groups and functional appendages affords immense (and often late-stage) diversification of the scaffolds. Altogether, 107 target molecules are reviewed along with 19 syntheses to illustrate the distinctive chemistries for creating and derivatizing scaffolds. The review covers the history of the field up through 2020, briefly touching on statistically derivatized carriers employed in immunology as counterpoints to the rationally assembled and derivatized scaffolds here, although most citations are from the past two decades. The scaffolds are used widely in fields ranging from pure chemistry to artificial photosynthesis and biomedical sciences.

Abstract Background In the surgical treatment of intrahepatic cholangiocarcinoma (ICC), postoperative complications may be predictive of long-term survival. This study aimed to identify an immune-nutritional index (INI) that can be used for preoperative prediction of complications. Patients and methods Multi-institutional data from 316 patients with ICC who had undergone surgical resection were retrospectively analysed, with a focus on various preoperative INIs. Results Severe complications (Clavien-Dindo grade III–V) were identified in 66 patients (20.8%), including Grade V complications in 7 patients (2.2%). Comparison of areas under the receiver operating characteristic curve (AUCs) among various INIs identified the prognostic nutritional index (PNI) as offering the highest predictive value for severe complications (AUC = 0.609, cut-off = 50, P = 0.008). Multivariate analysis revealed PNI

Abstract Background The appropriate loading protocol to improve masticatory performance (MP) is still unclear in elderly patients and two-implant overdentures (2-IODs) wearers. This study aimed to compare the long-term MP and maximum occlusal force of immediate loading (IL) and conventional loading (CL) of 2-IODs retained by magnetic attachments. Nineteen edentulous patients were randomly assigned to either an IL (n=10) or CL group (n = 9). In the IL group, the implant was loaded on the same day as insertion, whereas it was loaded 3 months after insertion in the CL group. Magnetic attachments were used to retain all overdentures to the implants. MP, measured by a piece of color-changeable chewing gum and a gummy jelly test, and maximum occlusal force, measured using an occlusal force measuring device, were assessed in both groups at baseline and at 3-, 4-, and 5-year follow-ups. Results No significant differences were observed in the MP and the maximum occlusal force between the IL and CL groups at any time point. However, a significantly higher MP was observed at the 3-year time point in the IL group (P = 0.036). The maximum occlusal force revealed a significant correlation with MP, both with the color-changeable chewing gum and gummy jelly at 5 years. Conclusion After long-term observation, no significant differences in MP and maximum occlusal force were observed between the IL and CL groups. However, compared to pre-implant insertion of the complete denture, the MP in the IL group significantly improved at 3 years. Furthermore, the maximum occlusal force was significantly correlated with MP at 5 years. Trial registration UMIN, UMIN000009889 . Registered on 28 January 2013.

Abstract The lung is the most common site of metastasis in patients with renal cell carcinoma (RCC). Metastatic RCCs, even those classified as stage I, can recur after >10 years. Therefore, it is critical to completely resect metastatic nodules. Here, we report the case of a 74‐year‐old man who underwent a nephrectomy for RCC and was diagnosed with lung metastasis 17 years later. The metastatic nodule was resected through complete thoracoscopic subsegmentectomy. He had previously undergone partial nephrectomy for clear cell renal carcinoma pT1bN0M0. During his annual follow‐up, a computed tomography scan revealed a pulmonary nodule. The intraoperative frozen section revealed a metastatic clear cell RCC. Thus, additional lobectomy was not performed. The postoperative course was uneventful with no complications. This case demonstrates that even early stage metastatic clear cell renal carcinoma can recur after over 17 years. Thoracoscopic segmentectomy is less invasive and can preserve pulmonary function.

Abstract Background The vertical thickness of the peri-implant mucosa is associated with the amount of post treatment marginal bone loss. However, the variations in mucosal thickness at the different edentulous sites have been sparsely documented. The purpose of the study was to conduct a survey of the frequency distribution of variations in mucosal thickness at the different sites of the edentulous alveolar ridge and to compare them according to gender. Our study included 125 partially edentulous patients having a total of 296 implant sites. Cone-beam computed tomography (CBCT) scans were obtained by placing a diagnostic template with a radiopaque crown indicator on the ridge to determine the mucosal thickness at the crest of the alveolar ridge. Results The mucosal thickness was 3.0±1.3 mm in the maxilla, which was significantly greater than the mucosal thickness of 2.0±1.0 mm in the mandible (p

Abstract Background During implant treatment in the maxillary molar area, maxillary sinus floor augmentation is often performed to ameliorate the reduced alveolar bone height attributable to bone remodeling and pneumatization-induced expansion of the maxillary sinus. However, this augmentation may cause complications such as misplaced implants, artery damage, and maxillary sinus mucosal perforation; infections like maxillary sinusitis; and postsurgical complications such as bone graft leakage and postoperative nasal hemorrhaging. To reduce the complications during maxillary sinus floor augmentation and postoperative infections, we performed retrospective investigations of various systemic and local factors that influence pre-operative sinus mucosal thickness (SMT) by using cone-beam computed tomography (CBCT). Subjects included patients who underwent maxillary sinus floor augmentation in an edentulous maxillary molar area with a lateral approach. Pre-operative SMT, existing bone mass, and nasal septum deviation were measured using CBCT images. Relationships between SMT and the following influencing factors were investigated: (1) age, (2) sex, (3) systemic disease, (4) smoking, (5) period after tooth extraction, (6) reason for tooth extraction, (7) residual alveolar bone height (RBH), (8) sinus septa, and (9) nasal septum deviation. Correlations were also investigated for age and RBH (p < 0.05). Results We assessed 35 patients (40 sinuses; 11 male, 24 female). The average patient age was 58.90 ± 9.0 years (males, 57.9 ± 7.7 years; females, 59.9 ± 9.4 years; age range, 41–79 years). The average SMT was 1.09 ± 1.30 mm, incidence of SMT > 2 mm was 25.0%, incidence of SMT < 0.8 mm was 50.0%, and the average RBH was 2.14 ± 1.02 mm. The factors that influenced SMT included sex (p = 0.0078), period after tooth extraction (p = 0.0075), reason for tooth extraction (p = 0.020), sinus septa (p = 0.0076), and nasal septum deviation (p = 0.038). Conclusions Factors associated with higher SMT included male sex, interval following tooth extraction < 6 months, periapical lesions, sinus septa, and nasal septum deviation. Factors associated with SMT > 2 mm were sex and reason for tooth extraction, while factors associated with SMT < 0.8 mm were time following tooth extraction and nasal septum deviation. Despite the limitations of this study, these preoperative evaluations may be of utmost importance for safely conducting maxillary sinus floor augmentation.

Background: Febrile urinary tract infection (fUTI) is the most common serious bacterial infection in children. Despite this, there have been no studies examining the clinical features of pediatric fUTI in Japan. The purpose of this study was to describe the clinical characteristics of fUTI in Japanese children. Methods: A multicenter, retrospective, observational study was conducted at 21 hospitals in Japan. Children under the age of 15 years who were diagnosed with fUTI between 2008 and 2017 were included. The diagnostic criteria were a temperature over 38 °C and the presence of a single bacterial pathogen in urine culture. Patient characteristics were obtained from medical records. Results: In total, 2,049 children were included in the study. The median age was 5 months, and 59.3% were male. It was found that 87.0% of the males and 53.2% of the females were under 1 year of age. The main causative pathogens identified were Escherichia coli and Enterococcus spp., accounting for 76.6% and 9.8% of infections, respectively. Conclusions: There was a male predominance of fUTI in Japanese children, particularly in infants. Enterococcus spp. were the second most frequent causative pathogen; therefore, Gram staining of urine samples is strongly recommended before initiating antibiotic therapy.